1. Field of the Invention
The present invention generally relates to the field of therapeutics. More specifically, the invention relates to methods for neuroprotection in the brain.
2. Description of the Related Art
The central nervous system (CNS) is particularly vulnerable to insults that result in cell death or damage in part because cells of the CNS have a limited capacity for repair. As a result, disorders of the CNS often result in debilitating and largely irreversible degradation of a patient's cognitive and sensorimotor functions. Conditions that result in nerve cell death and damage range from degenerative disorders (e.g., Alzheimer's disease), ischemic episodes (e.g., stroke), or trauma.
Injury to the central nervous system (CNS) is an important cause of death and disability worldwide. For example, stroke is the third leading cause of death and disability in the U.S., with an estimated incidence of 700,000 cases annually. Two-thirds of stroke patients survive the first year following stroke, for an average of seven years, leading to more than 4.8 million stroke survivors currently in the U.S. Stroke costs the U.S. economy in excess of $30 billion per year in terms of medical costs and lost wages.
After several hours, little can be done to prevent the direct damage to the CNS caused by CNS disorders. For example, stroke treatments must typically be administered within six hours of onset. Depending on where the injury occurs in the brain, patients may be paralyzed on one side, may lose the ability to speak or see, and may have difficulty walking, among other symptoms. Gradual recovery of these functions is common, although recovery may be incomplete, and depends on the size and location of injury, among other factors.
Since damaged brain tissue does not regenerate, recovery must come from the remaining intact brain, which reorganizes itself, or rewires, in order to compensate for some of the function lost by the damage. Indeed, studies in animals and humans provide ample evidence of such reorganization of brain function following stroke. In particular, remaining neurons in both the damaged hemisphere and in the opposite intact hemisphere grow new processes (both axons and dendrites) and form new connections (synapses), which most likely contribute to recovery.
Stroke treatment has focused on limiting the extent of damage within the first few hours. Stroke is generally caused by a blockage of an artery leading to the brain, resulting in the death of brain cells supplied blood by that blocked artery. Current treatments for stroke have centered on treatments to prevent arterial blockages (control of blood pressure, lipids, heart disease, etc.), and treatments to prevent brain damage once the blockage has occurred. These latter treatments include “thrombolytic agents” (“clot busters” such as tPA) to break up arterial clots, and “neuroprotective agents,” designed to protect brain tissue at risk for stroke. Such thrombolytic and neuroprotective agents must be administered within hours after the onset of stroke in order to be effective. Methods currently available for promoting recovery from CNS damage allow only partial recovery of neurological functions. In patients suffering from debilitating neurological deficits, incremental improvements in function may have a significant effect on quality of life. Given the large number of affected patients and the limitations of current methods, there is an urgent need for additional and improved methods to promote recovery from damage to the nervous system.
The classical role of astrocytes is to protect and support neurons. Astrocytes are present in significantly higher numbers than neurons in the adult brain and play an important role in brain homeostasis. Additionally, astrocytes are likely participants in information processing. Following synaptic activity, astrocytes buffer perisynaptic K+ and remove extracellular glutamate by means of ATP-dependent membrane transporters. During oxidative stress, neuronal glutathione levels (GSH) are rapidly depleted and its re-synthesis is dependent on GSH production in and efflux from astrocytes. These physiological functions require that astrocytes be capable of rapidly responding to changes in neuronal activity and requirements with increased metabolic activity.
Astrocytes express receptors for a variety of neurotransmitters that are released from either neurons or glial cells. ATP/ADP appears to be the predominant extracellular signaling molecule in astrocytes. Both metabotropic (P2Y) and ionotropic purinoreceptors (P2X) are expressed in astrocytes and activation of either receptor subfamily results in increased intracellular Ca2+. The metabotropic inositol triphosphate (IP3) signaling pathway provides a mechanism whereby local extracellular signals can be rapidly transduced into increased intracellular ATP. G-protein linked receptors increase the production of IP3, triggering release of Ca2+ from thapsigargin sensitive stores in the endoplasmic reticulum (ER). IP3-mediated Ca2+ release can, in turn, increase mitochondrial Ca2+ and consequently, increase respiration and ATP production. The production of intracellular ATP via Ca2+-induced activation of matrix dehydrogenases is very rapid, occurring at levels ten-fold faster than stimulation by feedback from ATP/ADP pools. Although mitochondrial Ca2+ uptake can increase ATP production, IP3-mediated Ca2+ release has also been shown to sensitize cells to apoptotic stimuli. Reports by Bernadi and co-workers suggest that this increased sensitivity, in part, can be attributed to Ca2+ sensitive sites on the adenine nucleotide translocator, which under some circumstances plays a role in the mitochondrial permeability transition. Thus, an ATP-mediated increase in intracellular Ca2+ release can signal either cell survival or cell death for an astrocyte.